New Publication - SG2285 A Novel Antitumour Prodrug
4th September 2009
Howard P.W. et al. (2009). Synthesis of a novel C2/C2' -aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate. Bioorganic & Medicinal Chemistry Letters 19 6463-6466
This publication details the synthesis of prodrug SG2285 a novel C2/C2'-aryl-substituted pyrrolobenzodiazepine (PBD) dimer.
SG2285 is the bisulphite prodrug of the PBD dimer of SG2202. The bisulphite groups significantly increase the water solubility of the molecule. However, once the molecule enters cells the bisulphite groups are removed allowing the PBD to cross-link DNA and kill tumour cells. SG2285 is active against a wide range of human tumour cell lines at picomolar levels of activity.
John A. Hartley et.al (2010 In press) SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer pro-drug with potent antitumor activity. Cancer research
SG2285 is a highly efficient DNA interstrand cross-linking agent, although the cross-links form more slowly than those produced by the parent imine dimer SG2202. Antitumour activity was demonstrated across a range of human tumour xenograft models. Cures were obtained in LOX melanoma and SG2285 was superior to irinotecan in the advanced stage colon model LS171T.
More information…
John A. Hartley et.al (2010 In press) SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer pro-drug with potent antitumor activity. Cancer research
Abstract:
The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble pro-drug of SG2202 whereby two bisulphite groups inactivate the PBD N10-C11 imines. Once the bisulphites are eliminated, the imine moieties can bind covalently in the DNA minor groove forming an interstrand cross-link.
SG2285 is potent in vitro against a panel of human tumour cell lines (mean GI50 20 pM, range 0.3-68,000 pM). SG2285 is highly efficient at producing DNA interstrand cross-links in cells, which form more slowly than those produced by SG2202. Using DNA repair-deficient cell lines, cellular sensitivity to SG2285 was shown to be dependent primarily on ERCC1 and homologous recombination repair. In 20 primary B-CLL samples the mean LD50 was 8.3+/-3.4 nM, significantly lower than in normal age-matched B- and T-lymphocytes. DNA interstrand cross-links were detectable after 8 hours increasing to 48 hours in B-CLL cells following 2 nM SG2285. Antitumor activity was demonstrated in all human tumor xenograft models studied. Cures were obtained in LOX melanoma following a single dose of 3, 1.5 or 0.75 mg/kg. In an advanced stage LS174T colon model it was superior to irinotecan when administered either as a single dose, qdx5 or q4dx3. Significant activity was also seen against SKOV-3 (ovarian) (tumor-free survivors), OVCAR-5 (ovarian), A549 (NSCLC), PC3 (prostate) and Bx-PC-3 (pancreatic). SG2285 is currently in preclinical development.
Howard P.W. et al 2009 - View more here: http://bit.ly/aljLNf
Hartley J.A. et al 2010 - View more here: http://bit.ly/agB31j